PROJECT SUMMARY/ABSTRACT Transforming growth factor-beta (TGF-?) is one of the most important growth factors involved in morphogenesis of ocular anterior segment tissues including corneal stroma, a transparent tissue layer responsible for acquiring normal vision. We examined the hypothesis that conditional ablation of Tgfbr2- mediated signaling pathway in keratocytes can perturb postnatal corneal development and homeostasis. We generated a novel Tgfbr2 keratocyte knockout mice, Tgfbr2Kera-ko. These mice display a severe corneal stromal thinning phenotype resembling keratoconus (KTCN) in humans, a progressive eye disease in which the normally round cornea thins and begins to bulge into a cone-like shape causing distorted vision. We hypothesize that the Tgfbr2 signaling (including Smad-dependent and/or Smad-independent) in keratocytes is indispensable for corneal morphogenesis and homeostasis. Tgfbr2Kera-ko mouse strain is a potential model to elucidate the molecular mechanism of TGF-? signaling pathway and its downstream target(s) in keratocytes for corneal development and homeostasis. To our knowledge, this mouse strain may be the first genetic-defined animal model for human KC research and therapy. We propose two specific aims to achieve these goals. Specific Aim 1: To elucidate the role of Tgfbr2-mediated signaling in mesenchymal keratocytes during corneal development and homeostasis. Specific Aim 2: To figure out the Smad-dependent or non-Smad pathway through which Tgfbr2 signaling takes place in the keratocyte to regulate corneal development and homeostasis. Impact: Completion of these proposed aims in two years will provide groundbreaking knowledge regarding the critical roles of TGF-? signaling in mesenchymal keratocytes during corneal development and homeostasis- serving as the basis for the long term goal of improving eye care and related ocular diseases like corneal ectasia (keratoconus). On an even greater scale, the information gained from the cornea can be harnessed in other tissue systems where mesenchymal TGF-? signaling is crucial for development, homeostasis, and wound healing.